Worldwide, every other second someone suffers a stroke, the #1 cause of disability in western countries. The catastrophic burden of stroke and the scarcity of evidence-based rehabilitation interventions to decrease disability from stroke represent a major challenge to global health care. There is a gap between studies in animals demonstrating rewiring of neuronal circuits and availability of neurorehabilitative strategies to restore independent living in the clinical domain. Basic infrastructure to implement research in stroke rehabilitation has been developed at the Neurostimulation Laboratory at Hospital das Clmnicas/ Sao Paulo University/ Fundagao Faculdade de Medicina, Brazil, in great part due to a previous successful R21 grant funded by NIH. A strong partnership was developed between the Neurostimulation Laboratory and the Human Cortical Physiology and Stroke Rehabilitation Section at NINDS. In the R21 grant, peripheral sensory stimulation (PSS) was applied to enhance effects of training in patients in with stroke. In PSS, electrical currents are delivered to peripheral nerves, in the absence of pain. Increase in sensory input by PSS enhances excitability of brain motor areas and can improve hand motor performance, as demonstrated by results from our R-21 grant and from other studies. Another painless emerging technique to enhance motor function is transcranial direct current stimulation (tDCS) that enhances brain excitability non-invasively. Most neuromodulation research to improve motor function in stroke has focused on patients with mild hand motor impairment. This grant proposal will build on results of the R-21, by using a novel approach to treat patients with moderate to severe hand weakness in the chronic phase after stroke, to whom there are virtually no universally accepted options to decrease hand disability. In these patients, electrical currents delivered to muscles in the form of functional electrical stimulation (FES) can assist movement performance and motor training. We will combine FES, PSS and tDCS in an innovative strategy. The first aim of this grant is to compare effects of a single session of FES in close association with either tDCS alone, PSS alone, tDCS + PNS or sham tDCS + sham PSS, on motor impairment of patients with moderate to severe upper limb weakness in the chronic phase after stroke. The second aim is to compare the effects of several sessions of the most powerful neuromodulation intervention according to results of Aim 1, and effects of placebo (sham PSS/tDCS) combined with FES + task-specific training, on the ability to perform activities of daily living. In Aim 2, the interventions will be administered over six weeks to two groups of adult stroke patients with moderate to severe hand weakness. The proposed paradigm represents a step forward to break barriers in translational research by means of a multidisciplinary link. The P.I., Dr. Conforto, chief of the Neurostimulatation Laboratory in Brazil, the middle-income country (MIC) institution, will collaborate with researchers from high-income country (HIC) institutions: Dr. Leonardo Cohen, an eminent researcher that leads the Human Cortical Physiology and Stroke Rehabilitation Section at Intramural NINDS; Dr. P. Hunter Peckham, a distinguished researcher and pioneer on FES, who is Professor of Biomedical Engineering at the Case Western Reserve University; Dr. Andre Machado, Director of the Center for Neurological Restoration and Assistant Professor of Surgery in the Neurosurgery Department at the Cleveland Clinic, who has extensive experience in neuromodulation protocols. The collaboration between MIC and HIC institutions will set the stage for advancing research on non-invasive cortical neuromodulation and biomedical engineering, needed to ripen strategies for stroke rehabilitation. Equipment and facilities are available at the MIC institution that will provide full support to this proposal. PUBLIC HEALTH RELEVANCE: Cerebrovascular disease is a major cause of disability worldwide. The catastrophic burden of stroke is more dramatic in low- and middle- income countries, and the scarcity of evidence-based rehabilitation interventions represents a major challenge to global health care. Upper limb weakness is frequent after stroke, but there is no universally accepted treatment to effectively improve hand function in patients with moderate and severe motor impairment. These are the patients in deepest need of rehabilitative interventions. This project addresses this important issue, by testing effects of a novel approach. We will non-invasively stimulate the brain and peripheral nerves in order to enhance effects of motor training aided by an electrical stimulation device in patients with moderate to severe hand weakness. This grant will set the stage to develop game-changer strategies for stroke rehabilitation valuable to low-, middle- and high-income countries.